The polymerization and sol-gel transformation of deoxyhemoglobin S will be inhibited by an unexplored mechanism in which the close approach of hemoglobin molecules necessary to initiate and propagate polymerization is prevented and the hemoglobin is allowed to remain fully functional. Peptides of the amino acid sequence present in the N-terminal portion of Band 3 of the human erythrocyte bind reversibly to hemoglobin A at the 2,3-DPG receptor locus. Binding to the deoxy conformation is much greater than to the oxy. The peptides extend deep into the cavity between the beta chains and, depending on length, protrude for varying distances beyond the confines of the tetrad. The interactions between fragments of the N-terminal cytoplasmic portion of Band 3 and hemoglobin S are comparable with those of hemoglobin A but the effect of such peptides on the polymerization of deoxy S has not been explored. It is postulated that 1) a 15 amino acid peptide of the same sequences as in the N-terminal cytoplasmic domain of Band 3 will enter the inter-betaS chain region a distance of 18 angstrom and protrude approximately 27 angstrom outside the molecule to occupy and occlude a hemispheric volume of 27 angstrom radius around the 2,3-DPG binding site of the betaS chains and 2) the protruding portion of the peptide will, by sheer bulk or by covering up specific interacting sites, prevent the 1-5 angstrom approaches that the surface beta 6 mutant and other contact areas must make to initiate polymerization. Additional steric impedance to hemoglobin S polymer formation may arise from 1) disordering of the beta chains in the 10-12 residues f the C-termini and in the 3 N-terminal amino acids before the A helix (Changes induced in hemoglobin A by the peptide), and 3) the formation of binary complexes of deoxyhemoglobin S molecules tethered together by the peptide in beta-to-beta chain apposition. These could not properly incorporate into the polymer. The peptides will be designed, synthesized, purified, and characterized: evaluation of reactions with hemoglobin will be by Csat, time-viscosity profile, physical properties of gel, P50, competitive binding with other polyanions, change in charge and M.W. The binding, reversibility, and steric interference will be optimized by varying the molar rations of peptide to hemoglobin, peptide length, amino acid sequence, an contour. Results will provide new data on nucleation, the polymerization reaction, and the structure of polymer and gel. A new class of inhibitors will be defined that may ultimately find applicability in controlling the intracellular polymerization basic to the pathophysiology and clinical manifestations of sickle cell disorders.